Plasmodium falciparum is the parasitic protozoan responsible for fatal malaria in humans. It causes about 300 million clinical case of malaria and 2-3 million deaths annually. There is no vaccine against malaria, so selection of drug resistant malaria parasites has been a major factor in increased malaria morbidity and mortality in the last two decades. The few drugs that have been developed are too expensive for routine use in malaria treatment in most developing countries where the main burden of disease is felt. Inhibitors of the enzyme dihydrofolate reductase (DHFR) like pyrimethamine have been excellent antimalarials, but point mutations in the target gene compromised its effectiveness. The PS series of drugs are biguanides that are metabolized to triazines that also inhibit the P. falciparum DHFR. In Phase I, we have shown that these triazines do not show cross-resistance to any of the previously tested inhibitors of the P. falciparum DHFR, pyrimethamine, cycloguanil or chlorcycloguanil. In addition, we have recently discovered that these compounds are effective inhibitors of the DHFR enzyme from P. vivax, the most prevalent human malaria parasite. A clinical candidate has been selected based on 90 day oral studies in mice. This proposal is to support the preclinical safety assessment to bring this candidate to the clinic, to continue the yeast genetics program providing field monitoring for the development of resistance, and to extend the mechanism of action studies.